Wiping an iPS Cell's Epigenetic Memory With TNT
New research from a coalition of Australian institutions suggests a method for cohesively resetting a cell's epigenetic memory.
Scientists from the Harry Perkins Institute of Medical Research, the Monash University, and the University of Adelaide have proposed an approach for reverting a cell's genes to their earliest stages of embryonic development.
Progress in the field of regenerative medicine to date has been hampered by the fact that while induced pluripotent stem cells (iPS cells) are very similar to natural cells, their genomes still carry the biological memories of the cells they were derived from.
These characteristics, or hangovers from their reprogramming, include epigenetic memory.
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However, the novel approach – which involves the dynamically-named transient-native-transient (TNT) reprogramming strategy – significantly reduces the differences between iPS cells and embryonic stem cells.
To understand what happens to somatic cells when they revert back to their embryonic state, the researchers applied a technique called genome-wide DNA methylation profiling.
This displayed the trajectory of epigenetic genes, which alter how the genes are expressed rather than the DNA itself.
Carrying out the same profiling technique on natural embryonic stem cells demonstrated the differences, with iPS cells containing more epigenetic changes than embryonic stem cells.
An Explosive Approach to Wiping Epigenetic Memory
Armed with this data, the researchers hit upon the TNT method, which stabilises the somatic cells as they transform by adding a step that resets the genome to that of an embryonic cell.
The TNT method was found to achieve a 71% success rate in extinguishing the differences between iPS cell genomes and natural embryonic stem cells.
By comparison, cells that underwent somatic cell nuclear transfer programming – the conventional method for correcting aberrations between iPS and embryonic stem cells – had a success rate of around 60%.
The approach was then used to reprogram TNT iPS cells into neurons, skeletal muscle cells, lung epithelial cells, and neural stem cells, with the aim of investigating whether this new method improved the quality of cells differentiated from iPS cells.
Treated stem cells consistently differentiated more efficiently than untreated stem cells, regardless of their origin prior to transformation.
Extracts from the study, published in Nature, explained that TNT reprogramming enhances the differentiation of iPS cells derived from multiple cell types.
The iPS cells produced as a result of epigenetic memory reprogramming are functionally more similar to human embryonic stem cells than conventional iPS cells.
Further down the line, TNT reprogramming may become the standard approach for stem cell reprogramming, with major implications for future treatment approaches in medical conditions such as heart disease and arthritis.
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